Anaesthetics, general + Opioids - Drug Interactions

The respiratory depressant effects of ketamine and morphinemay be additive. The dose requirements of desflurane,etomidate,propofol and thiopental may be lower after opioid use. Opisthotonos or grand mal seizures have rarely been associated with theuse of propofol with alfentanil and/or fentanyl. The effects of inhalational anaesthetics may be enhanced by opioid analgesics.

Clinical evidence,mechanism, importance and management

Opioid analgesics have been reported to reduce MAC values of inhalational anaesthetics. For example, fentanyl has been shown to lower MAC value of desflurane, probably in a dose-dependent manner, and this has been subject of a review (See reference number 1). The manufacturer notes that lower doses of desflurane are required in patients receiving opioids (See reference number 2). Remifentanil at a target-controlled plasma level of 1 nanogram/mL was found to decrease MAC of sevoflurane with nitrous oxide by 60%, and remifentanil 3 nanograms/mL produced a further 30 % decrease in MAC of sevoflurane (See reference number 3). Another study found that remifentanil (dose-dependently) decreased level of sevoflurane required to maintain anaesthesia (See reference number 4). However, 100 microgram/kg doses of morphine given during anaesthesia did not alter awakening concentration of sevoflurane (See reference number 5).

The manufacturer of etomidate recommends that dose of etomidate should be reduced in patients who have already received opioids (See reference number 6)

Ketamine is a respiratory depressant like morphine,but less potent, and its effects can be additive with morphine (See reference number 7). The manufacturer notes that prolonged recovery time may occur if opioids are used with ketamine (See reference number 8).

A study in 11 healthy subjects found that combination of ketamine and morphine almost abolished windup-like pain (progressive increase in pain intensity on repeated stimulation) in a skin burn injury. This effect was not found with either drug alone. Further, ketamine alone, but not morphine reduced area of secondary hyperalgesia of local burn and increased pain threshold, but combination did not appear to enhance this effect. The reduction of wind-up pain may be due to ketamineinduced prevention of acute tolerance to morphine (See reference number 9).

Another study in healthy subjects using various experimental pain models found that ketamine antagonised respiratory depressant effect of remifentanil. Remifentanil alone produced analgesic effects with all pain tests, but ketamine only enhanced effect of remifentanil on intramuscular electrical stimulation. Acute remifentanil-induced hyperalgesia and tolerance were detected only by pressure pain test and were not suppressed by ketamine. The combined effects of remifentanil and ketamine probably depend on type of pain (See reference number 10).

A 71-year-old man undergoing a minor orthopaedic operation was given a 500-microgram intravenous injection of alfentanil followed by a slow injection of propofol 2.5 mg/kg. Approximately 15 seconds after propofol, patient developed strong bilateral fits and grimaces, which lasted for 10 seconds. Anaesthesia was maintained with nitrous oxide/oxygen and halothane and there were no other intra- or postoperative complications. The patient had no history of convulsions (See reference number 11). Propofol has also been associated with opisthotonos (a spasm where head and heels bend backwards and body arches forwards) in two patients given fentanyl with or without alfentanil.(See reference number 12) There is a further report of opisthotonos during recovery from anaesthesia with alfentanil,propofol and nitrous oxide.(See reference number 13)Seizures have been reported in patients with and without epilepsy receiving propofol. They mainly occur during induction and emergence or are delayed after anaesthesia,suggesting that they may be caused by changes in cerebral levels of propofol,(See reference number 14) and postanaesthetic opisthotonos may be due to a propofol-induced tolerance to inhibitory transmitters (glycine and gamma-aminobutyric acid).(See reference number 13) Any association with opioid remains unknown, although it has been suggested that opioids may aggravate propofol-induced opisthotonos by antagonising actions of glycine.(See reference number 13)

Alfentanil has been found to reduce amount of propofol needed for loss of eyelash reflex and loss of consciousness, as well as increasing blood pressure fall produced by propofol (See reference number 15). Propofol inhibits both alfentanil and sufentanil metabolism causing an increase in plasma concentrations of these opioids,while alfentanil also increases propofol concentrations (reviewed by Vuyk(See reference number 16)and also described in more recent reports(See reference number 17-20)). Pretreatment with fentanyl may also decrease propofol requirements for induction of anaesthesia,(See reference number 16) and increase blood concentrations of propofol (See reference number 21). However,another study was unable to confirm an effect on blood propofol concentrations (See reference number 22). Remifentanil has been reported to reduce dose of propofol needed for anaesthesia and also to reduce recovery time (See reference number 23,24). Further,propofol and remifentanil caused dose-dependent respiratory-depression, which, during combined use, was synergistic (See reference number 25). One study using EEG-controlled dosing of propofol and remifentanil for anaesthesia found their pharmacodynamic effects were no more than additive (See reference number 26). Although remifentanil alone appears to be ineffective at countering response to stimuli, a study in healthy subjects has found that remifentanil can significantly reduce levels of propofol required to ablate response to shouting, shaking or laryngoscopy (synergistic effect), but effects on EEG measures were additive (See reference number 27). In another study in healthy subjects, synergy that occurred for both analgesic and hypnotic endpoints was found to be greatest at lower levels of drugs which for each drug alone would not be producing maximal effects (See reference number 28). Another study found changes in BIS (Bispectral Index) that suggested that remifentanil may have some hypnotic properties or that it can potentiate hypnotic effect of propofol (See reference number 29). It has been suggested that increased hypnotic effects may be due to a dose-dependent decrease in cardiac output by remifentanil, resulting in an increase in arterial and brain propofol with increased anaesthetic effect (See reference number 30). One pharmacokinetic study found that levels of remifentanil may be increased during concurrent propofol infusion,(See reference number 31) while another study found that concurrent propofol reduced volume of distribution and distribution clearance of remifentanil by 41%. It was concluded that although propofol affects remifentanil bolus dose pharmacokinetics,maintenance infusion rates and recovery times would not be significantly affected (See reference number 32).

The manufacturer notes that required induction dose of propofol may be reduced in patients who have received opioids, and that these drugs may increase anaesthetic and sedative effects of propofol, and also cause greater reductions in blood pressure and cardiac output. They also state that rate of propofol administration for maintenance of anaesthesia may be reduced in presence of supplemental analgesics such as opioids (See reference number 33).

Two reviews have discussed use of opioids and propofol in anaesthesia, their pharmacokinetic and pharmacodynamic interactions, and administration and monitoring techniques (See reference number 34,35).

Opioid analgesics would be expected to potentiate respiratory depressant effects of barbiturate anaesthetics. A study has found that dose of thiopental required to induce anaesthesia was reduced by pretreatment with fentanyl (See reference number 36)

Dale O. Drug interactions in anaesthesia: focus on desflurane and sevoflurane. Baillieres Clin Anaesthesiol (1995) 9,105–17.

Suprane (Desflurane). Baxter Healthcare Corporation. US Prescribing information,November 2005.

Albertin A,Casati A, Bergonzi P, Fano G, Torri G. Effects of two target-controlled concentrations (1 and 3 ng/ml) of remifentanil on MACBAR of sevoflurane. Anesthesiology (2004) 100, 255–9.

Coltura MJ-J,Van Belle K, Van Hemelrijck JH. Influence of remifentanil (Ultiva, GlaxoWellcome) and nitrous oxide on sevoflurane (Sevorane, Abbott) requirement during surgery.2001 Annual Meeting of the American Society of Anesthesiologists, New Orleans USA,2002. Abstract A-462.

Katoh T,Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. Can J Anaesth (1993) 40, 825–8.

Hypnomidate (Etomidate). Janssen-Cilag Ltd. UK Summary of product characteristics,February 2004.


Bourke DL,Malit LA, Smith TC. Respiratory interactions of ketamine and morphine. Anesthesiology (1987) 66, 153–6.


Ketalar (Ketamine hydrochloride). Pfizer Ltd. UK Summary of product characteristics,January 2006.


Schulte H,Sollevi A, Segerdahl M. The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans. Anesth Analg (2004) 98, 1574–80.

Luginbühl M,Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M.Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg (2003) 96, 726–32.

Wittenstein U,Lyle DJR. Fits after alfentanil and propofol. Anaesthesia (1989) 44, 532–3.

Laycock GJA. Opisthotonos and propofol: a possible association. Anaesthesia (1988) 43,


Ries CR,Scoates PJ, Puil E. Opisthotonos following propofol: a nonepileptic perspective and treatment strategy. Can J Anaesth (1994) 41, 414–19.

Walder B,Tramèr MR, Seeck M. Seizure-like phenomena and propofol. A systematic review.Neurology (2002) 58, 1327–32.

Vuyk J,Griever GER, Engbers FHM, Burm AGL, Bovill JG, Vletter AA. The interaction between propofol and alfentanil during induction of anesthesia. Anesthesiology (1994) 81, A400.

Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids and propofol.J Clin Anesth (1997) 9,23S–26S.

Ihmsen H,Albrecht S, Fechner J, Hering W, Schuttler J. The elimination of alfentanil is decreased by propofol. 2000 Annual Meeting of the American Society of Anesthesiologists, SanFrancisco USA, 2002. Abstract 531.

Mertens MJ,Vuyk J, Olofsen E, Bovill JG, Burm AGL. Propofol alters the pharmacokineticsof alfentanil in healthy male volunteers. Anesthesiology (2001) 94, 949–57.

Mertens MJ,Olofsen E, Burm AGL, Bovill JG, Vuyk J. Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics. Anesthesiology (2004) 100, 795–805.

Schwilden H,Fechner J, Albrecht S, Hering W, Ihmsen H, Schüttler J. Testing and modellingthe interaction of alfentanil and propofol on the EEG. Eur J Anaesthesiol (2003) 20, 363–72.

Cockshott ID,Briggs LP, Douglas EJ, White M. Pharmacokinetics of propofol in female patients. Studies using single bolus injections. Br J Anaesth (1987) 59, 1103–10.

Dixon J,Roberts FL, Tackley RM, Lewis GTR, Connell H, Prys-Roberts C. Br J Anaesth (1990) 64, 142–7.

O’Hare R,Reid J, Breslin D, Hayes A, Mirakhur RK. Propofol–remifentanil interaction: influence on recovery. Br J Anaesth (1999) 83, 180P.

Drover DR,Litalien C, Wellis V, Shafer SL, Hammer GB. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy inchildren. Anesthesiology (2004) 100, 1382–6.

Nieuwenhuijs,DJF, Olofsen E, Romberg RR, Sarton E, Ward D, Engbers F, Vuyk J, MoorenR, Teppema LJ, Dahan A. Response surface modeling of remifentanil-propofol interaction oncardiorespiratory control and bispectral index. Anesthesiology (2003) 98, 312–22.

Fechner J,Hering W, Ihmsen H, Palmaers T, Schüttler J, Albrecht S. Modelling the pharmacodynamic interaction between remifentanil and propofol by EEG-controlled dosing. Eur J Anaesthesiol (2003) 20, 373–9.

Bouillon TW,Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, Shafer SL. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance oflaryngoscopy, bispectral index and electroencephalographic approximate entropy. Anesthesiology (2004) 100, 1353–72.

Kern SE,Xie G, White JL, Egan TD. Opioid-hypnotic synergy. Anesthesiology (2004) 100, 1373–81.

Koitabashi T,Johansen JW, Sebel PS. Remifentanil dose/electroencephalogram bispectral response during combined propofol/regional anesthesia. Anesth Analg (2002) 94, 1530–3.

Ludbrook GL,Upton RN. Pharmacokinetic drug interaction between propofol and remifentanil? Anesth Analg (2003) 97, 924–5.

Crankshaw DP,Chan C, Leslie K, Bjorksten AR. Remifentanil concentration during target-controlled infusion of propofol. Anaesth Intensive Care (2002) 30, 578–83.

Bouillon T,Bruhn J, Radu-Radulescu L, Bertaccini E, Park S, Shafer S. Non-steady stateanalysis of the pharmacokinetic interaction between propofol and remifentanil. Anesthesiology (2002) 97, 1350–62.

Diprivan (Propofol). AstraZeneca. US Prescribing information,August 2005.

Lichtenbelt B-J,Mertens M, Vuyk J. Strategies to optimise propofol-opioid anaesthesia. Clin Pharmacokinet (2004) 43, 577–93.

Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions. Acta Anaesthesiol Belg (2001) 52,445–51.

Wang LP,Hermann C, Westrin P. Thiopentone requirements in adults after varying pre-induction doses of fentanyl. Anaesthesia (1996) 51, 831–5.

Thiopental Injection. Link Pharmaceuticals Ltd. UK Summary of product characteristics,January 2003.